Pharmaceutical package



Dec. 19, 1967 J. W. PULLMAN PHARMACEUTICAL PACKAGE Filed Dec. 27, 1965 FlG 2 FlG 3 INVENTOR. JOHN W. PULLMAN BY I ATTORNEYS United States Patent 3,358,825 PHARMACEUTICAL PACKAGE John W. Pullman, Lafayette, Califl, assignor to Cutter Laboratories, Berkeley, Calif. Filed Dec. 27, 1965, Ser. No. 516,584 7 Claims. (Cl. 206-63.2)

This invention relates to the packaging and storage of liquid pharmaceuticals and is more particularly concerned with the means for and method of packaging dextran solutions for storage and transportation.

Dextran of molecular weight 75,000 is a blood plasma substitute which has been in popular use for approximately fifteen years. During the last few years dextran of molecular Weight 40,000 to 45,000 has become more important. The 40,000 molecular weight dextran, as did its predecessor, functions as a plasma expander and also has been shown to prevent red cell clumping which often occurs as a result of shock, crash injuries, and other situations. Commonly, the dextran solution is infused directly into the patients blood vessels from the package in which it is supplied.

In conventional shipment and storage, the dextran is packaged in independent solution bottles quite frequently comprising bottles with rubber caps which may be punctured by hypodermic needles for sterilized withdrawal of the dextran from the container. In such solution bottles, there is normally provided an air space between the top of the liquid and the top seal or cap. The air space is necessary to provide a physical buffer which can mechanically absorb the effects of expansion and contraction of the liquid due to ambient temperature fluctuations.

Dextran solutions of all known molecular weights, but particularly dextran of molecular weight 40,000 when packaged in the aforesaid mode will form precipitates of dextran crystals, sometimes called fingernails, which render the product either unsuitable or undesirable for pharmaceutical uses such as direct infusion in a vein. The crystals to a great extent can be removed by heating the material or, in some cases by filtering; however, these procedures are not entirely satisfactory. It has also been reported that when dextran bottles are filled so that there is no air space the precipitation problem above referred to is substantially or completely eliminated. It is difficult, however, to provide a practical bottle which when completely filled will be physically stable under conditions of varying ambient temperature changes. It is obvious that as the temperature increases the liquid expands and vice versa. For practical distributions, therefore, a gas or air buffer zone is most desirable.

The present invention concerns itself with the discovery that the air space of the solution bottle, if maintained at a temperature equal to the average or central temperature of the liquid within the solution bottle, will result in the dextran solution being free of the precipitation above referred to.

The present invention also concerns simple means to regulate the temperature of the air space in the solution bottle so that the temperature of the air space is maintained approximately at the temperature of the dextran solution in the bottle, even during varying ambient temperature conditions whereby the dextran solution within the bottle under typical temperature conditions of storage and transportation will not form the solid precipitates previously encountered in identical solution bottles.

A further object of this invention is to provide a package for sealed solution bottles of the type in which the solution bottles are filled with solution to a predetermined level and an air or gas zone is disposed above the solution. The package of this invention includes at the top of the bottles a thermal insulator which covers the entire top and extends downwardly to approximately the level of liquid within the bottles with the bottom or liquid bearing portion of the bottles being maintained in relatively free thermal communication with ambient temperature conditions.

Dextran solutions, as other liquids, will change in temperature less rapidly than gas or air. In the present invention, the amount of insulation over the bottle air space is determined to provide an effective rate of temperature change for the gas or air equal to that of the dextran solution. The insulating material on the upper portion of the solution bottles, in effect, causes a delay in the effect of ambient variations on the air or gas buffer zone.

In the present invention, the thermal insulation around the gas or air zone renders the thermal changes of the air or gas zone substantially equal to the thermal changes of the liquid by insulating or delaying ambient changes from affecting the air or gas zone for a period of time equal to the differential time required for a similar thermal change to be effected in the liquid or gas.

Other objects, features, and advantages of the present invention will be more apparent after referring to the following specification and attached drawings in which:

FIG. 1 is a cross-sectional view of a package formed to accomplish the method and packaging requirements of the present invention;

FIG. 2 is a top cross-sectional view taken at line 22 of FIG. 1; and

FIG. 3 is a crosssectional view of a typical package for packaging a single solution bottle in the mode as explained in reference to FIGS. 1 and 2.

In FIGS. 1 and 2 there is provided a typical container for receiving solution bottles A. Bottles A may be regular glass bottle structures having rubber caps 15 with a top formed to be penetraable at 18 by a typical hypodermic type needle so that dextran liquid 20 filled to a liquid level 23 within bottles A can be removed without affecting the sterility of the contents within the bottles. In case lot packaging it is desirable that each of the bottles have the same approximate liquid level for reasons that are hereinafter described.

Between liquid level 23 and rubber cap 15 is the typical air space 25 forming the physical buffifer zone to allow for expansion and contraction of the liquid. The case, in this instance, of 12 bottles in its bottom section is formed of a cardboard or paperboard material includ' ing bottom 30, outside walls 31, and partitioning walls 32. The bottom, outside, and partitioning walls mechani' cally package the bottles in receiving compartments for restraining the bottles against breakage during shipment by preventing the bottles from making a bottle to bottle contact. The paperboard or cardboard forming the receiving compartment has relatively low thermal insulation properties.

A preformed body of foamed polyurethane indicated at block B is formed with common expansion molding techniques to provide receiving areas for the upper portions of the bottles so that the block B, when fitted onto the container, will intimately contact the top portions of all the bottles within the container. The bottom portion 35 of block B extends to a point coincident liquid level 23 of the dextran in the respective bottles A. As shown in the drawing, this may be slightly below the liquid level but should not be too far below the level to form any substantial insulation of the liquid. The top of block B is covered by an extension of typical cardboard or paperboard 38 to complete the package.

In application, under conditions of rising temperature, the ambient atmosphere has little trouble in passing through the cardboard to the bottom portions of bottles A and, thereby, immediately, physically acts with the bottle and the liquid to cause a gradual rise of the average liquid temperature of the dextran. The same ambient condition, of course, acts with block B, but due to the highly efficient insulating properties of the polyurethane there is a considerable time delay before the ambient temperature rise can pass through block B to effect a similar temperature rise of the upper portion of the bottle occupied by air space 25. It is here apparent that, normally, liquid will react slower to ambient conditions in effectively changing temperature than gas or air, thus, the differential of temperature change between gas and liquid is equalized by the polyurethane block B so that gas in air space 25 will effectively rise in temperature at the same rate as the average temperature of liquid 20 when the amount of insulation in block B is selected with this objective in mind.

It is obvious that when the ambient temperature is brought to a lower level that a reverse procedure will take place in the same equilibrium. With packages of the aforesaid type, it has been found that dextran, and particularly the more troublesome dextran of molecular weight of approximately 40,000, can be stored in conditions of changing ambient temperatures throughout a relatively wide range. It has been established that such ambient temperature changes including conditions of refrigeration to substantial heating without development of the typical precipitates which have long characterized the dextran molecular weight 40,000 when conventionally stored or packaged.

The actual dimensions of the polyurethane should be selected so that the insulating properties of the polyurethane is sufiicient to restrict the temperature difference between the air space in the bottle and the temperature of the midpoint in the liquid to be as low as possible. It has been found that when the temperature diflferential is below 1 centigrade, satisfactory precipitation elimination is obtained, although possibly greater temperature differential may give excellent results also.

As can be seen in FIG. 3, the packaging need not be confined to case lots and may be applied to single bottle storage. In FIG. 3, a bottle 40 is provided in a paperboard container 42 in which bottle 40 is of similar construction to bottle A. A polyurethane block &5 is premolded to the form of the top of bottle 40 and is fitted over the top of the bottle to extend slightly below the liquid level 46 of the dextran 48 within the bottle. As previously noted, it is desirable that the polyurethane make as intimate and close contact as possible to maintain the most effective thermal insulation.

While the above invention has been described in relation to preformed polyurethane insulating blocks, it is obvious that any good thermal insulator can be applied to the top of the bottles and it is the intent of the present invention that the insulation be sufiiciently greater at the top of the bottle than at the bottom to cause an equalizaion of temperature changes within the bottle of the liquid and the air under conditions of changing ambient temperatures.

While one embodiment of this invention has been shown and described, it will be apparent that other adaptations and modifications can be made without departing from the true spirit and scope of the invention.

What is claimed:

1. A method of storing dextran solution within a container having gas at the top portion of said container including the steps of thermally insulating the top portion of the container from ambient conditions from a position adjacent the liquid level within the container upwardly to a greater extent than from the liquid level downwardly, the thermal insulation dilferential being to such an extent that the temperature dilferential within the container of the liquid and of the gas is maintained sufliciently low to prevent precipitation of the dextran throughout wide variations of ambient temperatures.

2. The method of claim 1 and wherein said temperature differential is less than about 1 centigrade.

3. A packaging container carrying a dextran solution at a predetermined liquid level within the container and a gas space between the predetermined liquid level and the sealed top of the container comprising a thermal insulating member mounted in intimate contact around the top portion of said container from a point substantially coincident with the predetermined liquid level upwardly, the bottom portion of said container from a point substantially coincident the predetermined liquid level in the container downwardly being maintained under less thermal insulation than the upper portion, said insulating member having thermal insulative properties sufficient to delay thermal changes of the gas within said containers to equalize temperature changes of the gas with temperature changes of the liquid within said container.

4. A packaging according to claim 3 and wherein said dextran is approximately molecular weight 40,000.

5. A thermal compensating packing for containers partially filled with liquid dextran and the remaining portion of the container being filled with gas comprising package means to support said container and thermal insulating means mounted within said package means immediately against the top portion of said container to thermally insulate the top portion of said container more than the bottom portion from temperature changes due to contact of the packaging with changing ambient temperature conditions.

6. A packing according to claim 5 and wherein the lower juncture of said thermal insulating means is at a point coincident with the liquid level in said container.

7. A packing according to claim 5 and wherein said thermal insulating means has thermal insulating properties to delay the rate of ambient temperature in changing the temperature of the gas within said container to substantially equal the rate of temperature change of the liquid within the container.

References Cited UNITED STATES PATENTS 2,176,275 10/1939 Pierce 217l9 2,944,695 7/1960 Yusz 217l9 JOSEPH R. LECLAlR, Primary Examiner.

L. G. MANCENE, Assistant Examiner. 

1. A METHOD OF STORING DEXTRAN SOLUTION WITHIN A CONTAINER HAVING GAS AT THE TOP PORTION OF SAID CONTAINER INCLUDING THE STEPS OF THERMALLY INSULATING THE TOP PORTION OF THE CONTAINER FROM AMBIENT CONDITIONS FROM A POSITION ADJACENT THE LIQUID LEVEL WITHIN THE CONTAINER UPWARDLY TO A GREATER EXTENT THAN FROM THE LIQUID LEVEL DOWNWARDLY, THE THERMAL INSULATION DIFFERENTIAL BEING TO SUCH AN EXTENT THAT THE TEMPERATURE DIFFERENTIAL WITHIN THE CONTAINER OF THE LIQUID AND OF THE GAS IN MAINTAINED SUFFICIENTLY LOW TO PREVENT PRECIPITATION OF THE DEXTRAN THROUGHOUT WIDE VARIATIONS OF AMBIENT TEMPERATURES. 